title: Increased cytoplasmic localization of p27(kip1) and its modulation of RhoA activity during progression of chronic myeloid leukemia.
abstract: The role of p27(kip1) in Chronic Myeloid Leukemia (CML) has been well studied in relation to its function as a cell cycle inhibitor. However, its cytoplasmic function especially in CML remains to be seen. We studied the localization of p27(kip1) and its function during the progression of CML from chronic to blast phase. Our investigations revealed an increased localization of p27(kip1) in the cytoplasm of CD34(+) cells in the blast phase compared to chronic phase. Cytoplasmic p27(kip1) was found to modulate RhoA activity in CD34(+) stem and progenitor cells. Further, RhoA activity was shown to be dependent on cytoplasmic p27(kip1) which in turn was dependent on p210(Bcr-Abl) kinase activity. Interestingly, RhoA activity was observed to affect cell survival in the presence of imatinib through the SAPK/JNK pathway. Accordingly, inhibition of SAPK/JNK pathway using SP600125 increased apoptosis of K562 cells in presence of imatinib. Our results, for the first time, thus reveal a crucial link between cytoplasmic p27(kip1), RhoA activity and SAPK/JNK signalling. To this effect we observed a correlation between increased cytoplasmic p27(kip1), increased RhoA protein levels, decreased RhoA-GTP levels and increased SAPK/JNK phosphorylation in blast phase CD34(+) cells compared to chronic phase CD34(+) cells.
authors.affiliation: Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, West Bengal, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Roy
authors.forename: Lakshmishri
authors.initials: L
authors.lastname: Lahiry
authors.forename: Debasis
authors.initials: D
authors.lastname: Banerjee
authors.forename: Malay
authors.initials: M
authors.lastname: Ghosh
authors.forename: Subrata
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001752:Blast Crisis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000873:Anthracenes; D018952:Antigens, CD34; C436291:CDKN1B protein, human; D047428:Protein Kinase Inhibitors; C066737:RHOA protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; C432165:pyrazolanthrone; D006160:Guanosine Triphosphate; D016044:Fusion Proteins, bcr-abl; D048670:MAP Kinase Kinase 4; D020742:rhoA GTP-Binding Protein